APPLICATION OF QbD IN TABLET DOSAGE FORM MANUFACTURING

Assignment No. -06

(Date: 25/03/2024)
Presented By:
Mr. Pratik Chandu Jogi
First Year M Pharm Sem –II
Roll No. -08
Guided By:
Mrs. Dr. N. M. Bhatia
Head of Quality Assurance,
Department of Pharmaceutical Quality Assurance

Pharmaceutical Quality Assurance

BHARATI VIDYAPEETH, College of Pharmacy, Kolhapur
2023-24
INTRODUCTION:

The traditional approach of formulating a new drug product is an exhaustive task

and involves several resources like man, money, time, and experimental efforts.
While using this Quality by Design (QBD) approach, one can get the
pharmaceutical product of the desired (best) quality by minimizing the above
resources and knowing the influence of one factor over the desired associated
process. Hence aim of this study is the understanding of QBD approach to design
products and manufacturing processes to get the desired pharmaceutical product.
QBD follows the concepts of ICH guidelines (Q8, Q9 & Q10) which are essential
for processing a pharmaceutical process. In this presentation, we will focus on
QBD for immediate-release dosage forms.

OBJECTIVE:
To improve the robustness of a core tablet for a novel modified release oral solid
dosage form using Quality by Design (QbD) principles.

How QbD came to Pharma?

Quality by Design (QbD) is a revolutionary concept in the pharmaceutical

industry, marking a significant shift from traditional quality control methods to a
more systematic and proactive approach to quality assurance. The concept, which
was introduced and developed by Joseph Juran in various sectors, has been adapted
and refined for pharmaceuticals, where it emphasizes the safety and efficacy of
drug products for patients.
The Food and Drug Administration (FDA) played a pivotal role in the evolution of
QbD. In 2004, the FDA launched the "Pharmaceutical CGMPs for the 21st Century
– A Risk-Based Approach," encouraging the industry to adopt a more rational and
flexible attitude toward pharmaceutical development. This initiative was a
historical milestone, signaling a new era where the identification of potential risks
and their mitigation became central to product development. The FDA's
endorsement of QbD provided pharmaceutical companies with the opportunity to
develop drugs based on a deep understanding of the product and process, shifting
the focus from final product testing to building quality throughout the development
process.
The significance of QbD lies in its comprehensive framework, which includes the
QTPP, Critical Quality Attributes (CQAs), and the use of Design of Experiments
(DOE) to establish a design space. This framework is supported by the
International Council for Harmonisation (ICH) guidelines, particularly ICH Q8,
which defines QbD as "a systematic approach for product development that begins
with predefined objectives and emphasizes product and process understanding and
process control, based on sound science and quality risk management." The ICH
guidelines, along with Q9 (Quality Risk Management) and Q10 (Pharmaceutical
Quality System), form the foundation for modern pharmaceutical development
practices.
The adoption of QbD has transformed the pharmaceutical landscape by reducing
out-of-specification results, facilitating easier transfer to manufacturing sites, and
ultimately ensuring a higher level of product quality. By integrating QbD
principles, companies can gain regulatory flexibility and a competitive edge, while
also committing to the highest standards of patient safety and product efficacy. As
the industry continues to evolve, QbD stands as a testament to the ongoing pursuit
of excellence in pharmaceutical quality and innovation.

QbD in Pharma
The FDA's endorsement of QbD was a call to action for pharmaceutical companies
to design quality into their products from the outset rather than relying on end-
product testing. By identifying and controlling potential risks in the development
and manufacturing processes, QbD aims to ensure that each product meets its
intended design criteria and patient needs.
The significance of QbD lies in its comprehensive framework, which is guided by
the International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) guidelines, particularly ICH Q8, Q9, and
Q10. These guidelines outline a systematic approach to development, emphasizing
product and process understanding and control based on sound science and quality
risk management. The QbD framework involves defining a QTPP that outlines the
necessary efficacy and safety levels of a drug product. CQAs are then identified,
which are physical, chemical, biological, or microbiological properties that should
be within an appropriate limit to ensure the desired product quality.
The FDA's role in shaping QbD has been pivotal, providing guidance, examples,
and training to facilitate the industry's understanding and implementation of this
approach. The adoption of QbD has not only improved the quality and efficacy of
pharmaceutical products but also provided regulatory flexibility, fostering
innovation in drug development. As the industry continues to evolve, QbD stands
as a testament to the FDA's commitment to enhancing pharmaceutical quality
through a risk-based approach.

The QbD framework is a systematic approach to pharmaceutical development that

begins with predefined objectives and emphasizes a thorough understanding of
both product and process, coupled with sound science and quality risk
management. The objective of QbD is to ensure the quality of pharmaceuticals by
design, rather than relying solely on testing the final product. This approach is
rooted in the ICH guidelines, which provide a comprehensive structure for
implementing QbD in the pharmaceutical industry.
QbD's framework is built upon several foundational elements: the QTPP, CQAs,
and the use of Design of Experiments (DOE) to establish a design space. The
QTPP is a summary of the quality characteristics of a drug product that ideally will
be achieved to ensure the desired quality, taking into account safety and efficacy.
CQAs are the physical, chemical, biological, and microbiological attributes that are
critical to ensuring that the product meets its intended profile.
A significant shift from Quality by Testing (QbT) to QbD has been advocated by
regulatory agencies like the FDA. Under the QbT paradigm, quality was primarily
assessed by testing finished products, with little emphasis on understanding the
effects of manufacturing processes and inputs on product quality. QbD, however,
encourages a more proactive approach to quality. It involves identifying variables
that can affect CQAs and ensuring control over these variables within the design
space—the range of conditions under which products can be produced to meet
quality requirements.
The design space is established through DOE, which allows for a detailed
understanding of the interactions between various input variables. By mapping
these interactions, companies can predict the impact of changes in inputs on the
final product quality. This knowledge enables manufacturers to make informed
decisions that enhance efficiency, reduce waste, and ensure consistent quality.
QbD framework marks a transition to a more scientific, risk-based, and data-driven
approach to pharmaceutical development, aligning with the modern regulatory
emphasis on process understanding and control.
General Background:
As stated in the International Conference on Harmonization Harmonized Tripartite
Guidance on Pharmaceutical Development, ICH Q8 (R2), “Pharmaceutical
development aims to design a quality product and its manufacturing process to
deliver the intended performance of the product consistently.”1 Several tools are
available as guidance issued by the FDA such as “Quality Systems Approach to
cGMP Manufacturing”2 that includes ideas such as Quality by Design (QbD) in
the development process. This guidance, amongst others, lay the framework for the
expectations of regulatory reviewers in their examination of client submittal
documentation.

This project involved first the technical transfer of a formulation and process of a
novel modified release oral solid dosage form (i.e. an active core tablet with a
series of coatings that modified the release and delivered additional quantities of
the same active ingredient) that was originally manufactured at a relatively small
scale. The next step was a scale-up of the process to commercial scale but due to
time constraints not all of the unit operations had been completely optimized. Upon
discovering processing issues such as relatively high friability and low breaking
strength of the core tablets the client agreed to proceed with optimization utilizing
principles of QbD.

The first step of the QbD process was to establish a Quality Target Product Profile
(QTPP) for the core tablets. The second step was to determine the Critical Quality
Attributes (CQA) of the core tablets. The third step incorporated a risk assessment
exercise to identify the Critical Processing Parameters (CPP). The final step
involved drafting an informal Design of Experiments (DOE) to determine optimal
settings of the CPPs for the critical high-shear wet granulation process.

METHODOLOGY:
• Materials:
Active Pharmaceutical Ingredient (API) X, (Supplied by client)
Microcrystalline Cellulose, NF/EP (Avicel ® PH 102 and PH 200, supplied
 by FMC)
Partially Pregelatinized Starch, NF (Starch 1500® supplied by Colorcon)
Croscarmellose Sodium, NF/EP (Ac-Di-Sol ® SD-711 supplied by FMC)
Magnesium Stearate, NF/EP, (Non-bovine, supplied by Mallinckrodt)
Various reagent-grade chemicals and solvents to execute required analytical
testing
• Manufacturing Equipment:
TK Fielder PMA-100 High Shear Granulator w/ Pressurized Spray Pot
O’Hara FBDG-30 Dryer with 100-liter bowl
Fitzpatrick Fitzmill, Model M
15 ft3 Tote Blender
Manesty Unipress equipped with 0.25” round standard concave tooling
• Analytical Equipment (Physical testing only)
USP <1216> Compliant Tablet Friability Tester
USP <1217> Compliant Tablet Breaking Force Tester
Based on the relatively late stage in the development cycle, the client agreed that
neither the core tablet formulation nor the unit operations used in its manufacture
could be changed. See Figure 1 below for a flowchart of the core tablet
manufacturing process.

Dry Mix X, Avicel PH 102, Starch 1500 and % of Ac-Di-Sol in 100 liter High
Shear Granulator (multiple portions)

Granulate Dry Mix in 100 liter High Shear Granulator (multiple portions)
(Water added from Pressurized Spray Pot)

Dry Wet Mass in Fluid Bed Dryer Equipped with 100 liter Bowl (multiple
portions)

Pass Dried Granulation through a High-Energy Mill (multiple portions)

Combine All Portions and Blend in a Low-Shear Tumble Blender

Blend Granules with Extragranular Excipients and Lubricant in Low-Shear

Tumble Blender

Compress Lubricated Blend into Tablets on a Rotary Tablet Press

In-process data gathered during the compression process indicated that the core
tablets had excellent weight control. However, even though the core tablets had
satisfactory friability to pass USP <1216> (Not more than 1.0% 3) the team agreed
that they would not be able to withstand the rigors of downstream coating in a
standard side-vented coating pan. The team further agreed that optimization on the
entirety of the core tablet manufacturing process was necessary using QbD
principles.
The first step of the optimization process using QbD principles was to establish a
Quality Target Product Profile (QTPP) for the core tablets themselves. Based on
the phase of work involved several elements of the QTPP had already been
established, such as the fact that the final dosage form was going to be a modified
release product with a novel coating scheme to allow for immediate and delayed
release of X. However a more formalized declaration of QTPP specific to the core
tablet itself had not. See Table 2 below for the QTPP for the core tablets
themselves.

The next step of the optimization process using QbD principles was to utilize the
QTPP above to derive a set of Critical Quality Attributes (CQA) of the Core
tablets. The CQA would be based on empirical evidence derived from previous
experimentation as well as similar experiences with other products. See Table 3
below for the CQA of the core tablets.
Using the attributes given above the team organized a set of Critical Process-
Parameters (CPP) utilizing a risk-based approach to all of the upstream unit
operations. This was based on previous experience with this project as well as
other similar dosage forms with equivalent or similar equipment trains. See Table 4
for CPP using a risk-based model of potential effects on CQA from above.
To build on previous experiments already performed, an abbreviated Design of
Experiments consisted of examination of only two of the CPP’s that had not been
already optimized. The two variables to be examined were granulating liquid
amount and post-spray wet-massing time. An full factorial experimental design
based on two factors with three settings (32) was agreed to, but with one
experiment left out (Medium Liquid Amount, Low Wet Mass Time) because that
had been evaluated in previous work and found to give unsatisfactory tablet
physical characteristics. Factor levels were defined as such:

Liquid Amount: Low = 8.500 kg, Medium = 9.000 kg, High = 9.500 kg
Wet Mass Time: Low = 2 minutes, Medium = 4 minutes, High = 6 minutes

See Table 5 below for factors for the abbreviated experimental design.

RESULTS:
CQA’s listed in Table 3 were evaluated for each experiment in the DOE and
compared to previously generated data for acceptability and improvement. See
Table 6 below for a summary of results from each experiment.

Conclusion
The QbD initiative, spearheaded by regulatory bodies such as the FDA, has set a
new standard for pharmaceutical development. It marks a departure from
traditional empirical approaches, advocating for a systematic, risk-based strategy
that aligns with the modern pharmaceutical landscape's complexity and regulatory
expectations. The future outlook for QbD is promising, as it continues to gain
traction across the industry, with a growing emphasis on comprehensive
understanding and control of manufacturing processes and product design.
The impact of QbD is multifaceted, offering significant benefits such as enhanced
product quality, increased manufacturing efficiency, and reduced time to market.
By adopting QbD principles, companies can achieve a deeper understanding of
their products and processes, leading to more robust product development and a
proactive approach to quality assurance. This, in turn, facilitates a more dynamic
regulatory environment where flexibility in manufacturing is matched with
stringent quality standards.